Cephalotaxanes are alkaloids extracted from skins, stems, leaves and seeds of Cephalotaxus fortunei Hook and other related species, such as Cepholotaxus sinensis Li, C. hainanensis and C. wilsoniana, including C. oliveri mast and C. harringtonia. Cephalotaxanes exhibit a unique structure, as shown in FIG. 1. Although cephalotaxine (wherein X in FIG. 1 is —OH) is abundant in C. harringtonia, it is devoid of biological activity. The presence of an ester side chain at C-3 appears to be critical to the antitumor potency.
Homoharringtonine (4-methyl-2-hydroxy-2-(4-hydroxy-4-methylpentyl), “HHT”) is the butanediocate ester of cephalotaxine. HHT is a naturally occurring cephalotaxine compound and has the structure shown in FIG. 2.
Reports suggest that HHT can be chemically synthesized with purity greater than 99.8% and total related impurity less than 0.5% (see L. Keller, et. al., Tetrahed. Lett., 42, 1911-1913 (2001)); international publication WO 02/32904 A1). Although at least 50% of Cephalotaxus alkaloids are cephalotaxine, the use of cephalotaxine as a source for semi-synthesis of HHT has not yet been economically justified.
HHT can also be prepared from cultured cells of C. harringtonia (U.S. Pat. No. 4,152,214). However, unlike preparations from cultured cells, whole plant-derived HHT has been clinically tested in various cancers including a number of forms of leukemia and preleukemic conditions, such as myelodysplastic syndrome (MDS). Furthermore, HHT derived from whole plants has been widely used in China as the front-line chemotherapy for acute myeloid leukemias, particularly acute promyelocytic leukemia (APL). There is little data on efficacy and toxicity of the chemically synthesized or tissue culture derived HHT.
Also, like most anticancer agents, HHT has dose-limiting toxicities, including myelosuppression, cardiotoxicity, and hypotension. Therefore, it is highly desirable to improve the dosage form of the drug, dosage amounts, and schedule of administration. Thus, improvements are sought to improve efficacy, reduce side effects, improve quality of life and increase survival of patients.
For naturally occurring products like HHT, it is desirable to increase the purity of HHT preparations away from related analogs, as well as reduce or eliminate additives, preservatives or excipients used to make the agent more pharmaceutically acceptable. More purified preparations will reduced physiologic stresses arising from the metabolic processing of or physiological responses to unwanted impurities and undesirable excipients. For example, additives such as sodium bisulfite, used as an antioxidant in pharmaceutical preparations, are known to cause allergic or hypersensitivity reactions in some patients. This also occurs for pharmaceutical diluents such as cremophor EL. Moreover, mannitol, a pharmaceutical excipient, can cause hypotension for some patients.
The National Cancer Institute conducted clinical trials in cancer chemotherapy using a lyophilized HHT product, provided as a sterile 10-mg vial. Mannitol (50 mg) and hydrochloric acid were included in the vial. The intact vials required frozen storage (at −10° C. to −20° C.). The lyophilized HHT in vials was to be reconstituted with 4.9 mL of 0.9% Sodium Chloride Injection, USP, to obtain a solution containing HHT at 2 mg/mL and having a pH of 3 to 5. The act of reconstitution could be problematic if improperly performed.
An object of the present invention was to provide a stable, therapeutically acceptable, intravenously injectable dosage form of HHT that does not require lyophilization and reconstitution, and that can be packaged and shipped as a single vial instead of a dual-vial package.
It is another object of the present invention to provide new methods and compositions for administering HHT for periods different from current dosage forms, and to provide new administration schedules to improve efficacy and reduce side-effects associated with drug treatment.